BACKGROUND AND PURPOSE: Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. METHODS: C57Bl/6, TNF(-/-), interferon (IFN) regulatory factor 7(-/-), or type I IFN receptor (IFNAR)(-/-) mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hours before middle cerebral artery occlusion. Infarct volume and functional outcome were determined after reperfusion. Plasma cytokine responses and induction of mRNA for IFN-related genes in the brain were measured. IFNAR(-/-) mice also were treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist before middle cerebral artery occlusion and infarct volumes measured. RESULTS: The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF(-/-) mice, indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7(-/-) and IFNAR(-/-) mice failed to be protected, implicating a role for IFN signaling in TLR7-mediated protection. CONCLUSIONS: Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
BACKGROUND AND PURPOSE: Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. METHODS: C57Bl/6, TNF(-/-), interferon (IFN) regulatory factor 7(-/-), or type I IFN receptor (IFNAR)(-/-) mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hours before middle cerebral artery occlusion. Infarct volume and functional outcome were determined after reperfusion. Plasma cytokine responses and induction of mRNA for IFN-related genes in the brain were measured. IFNAR(-/-) mice also were treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist before middle cerebral artery occlusion and infarct volumes measured. RESULTS: The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF(-/-) mice, indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7(-/-) and IFNAR(-/-) mice failed to be protected, implicating a role for IFN signaling in TLR7-mediated protection. CONCLUSIONS: Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
Authors: Fang Hua; Jing Ma; Tuanzhu Ha; Jim Kelley; David L Williams; Race L Kao; John H Kalbfleisch; I William Browder; Chuanfu Li Journal: J Neuroimmunol Date: 2008-06-27 Impact factor: 3.478
Authors: Javier R Caso; Jesús M Pradillo; Olivia Hurtado; Pedro Lorenzo; María A Moro; Ignacio Lizasoain Journal: Circulation Date: 2007-03-19 Impact factor: 29.690
Authors: Holly L Rosenzweig; Manabu Minami; Nikola S Lessov; Sarah C Coste; Susan L Stevens; David C Henshall; Robert Meller; Roger P Simon; Mary P Stenzel-Poore Journal: J Cereb Blood Flow Metab Date: 2007-02-28 Impact factor: 6.200
Authors: M Paula Longhi; Christine Trumpfheller; Juliana Idoyaga; Marina Caskey; Ines Matos; Courtney Kluger; Andres M Salazar; Marco Colonna; Ralph M Steinman Journal: J Exp Med Date: 2009-06-29 Impact factor: 14.307
Authors: Seija Lehnardt; Sabrina Lehmann; David Kaul; Katharina Tschimmel; Olaf Hoffmann; Sabine Cho; Christina Krueger; Robert Nitsch; Andreas Meisel; Joerg R Weber Journal: J Neuroimmunol Date: 2007-09-12 Impact factor: 3.478
Authors: Sung-Chun Tang; Thiruma V Arumugam; Xiangru Xu; Aiwu Cheng; Mohamed R Mughal; Dong Gyu Jo; Justin D Lathia; Dominic A Siler; Srinivasulu Chigurupati; Xin Ouyang; Tim Magnus; Simonetta Camandola; Mark P Mattson Journal: Proc Natl Acad Sci U S A Date: 2007-08-10 Impact factor: 11.205
Authors: Susan L Stevens; Thomas M P Ciesielski; Brenda J Marsh; Tao Yang; Delfina S Homen; Jo-Lynn Boule; Nikola S Lessov; Roger P Simon; Mary P Stenzel-Poore Journal: J Cereb Blood Flow Metab Date: 2008-01-09 Impact factor: 6.200